3Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, Finland

The review article entitled "Diagnosis and management of vitamin D deficiency" by Pearce [1] begun a vivid discussion in this journal. The general trend in those papers is that a significant vitamin D fortification is needed and serum concentrations of 25OHD3 should 75 nmol/L or more [2]. The comments cover several important aspects. However, two important aspects of vitamin D endocrinology were not covered: 1. The feedback systems in vitamin D endocrinology 2. The known risks of a slightly elevated serum concentrations of 25OHD3.

For more than two decades, a reciprocal feedback between 25OHD3 and 1,25(OH)2D3 has been known and the metabolic clearance rate seems to be the explanation, because 24-metabolites increase in the serum [3-5], but also the rate of synthesis of the respective metabolite might be affected. Since 25OHD3 is known as an inactive precursor metabolite, these findings were not understood before our recent study demonstrating the hormonal activity of 25OHD3 [6] and its synergistic action with 1,25(OH)2D3 [7]. Thus, 1,25(OH)2D3 and 25OHD3 act via the same nuclear receptor, VDR and synergistically at their physiological concentrations. Fig. 1 shows the induction of mRNA of 24-hydroxylase (CYP24A1) in a highly sensitive mouse kidney cells lacking 1Î±-hydroxylation. A strong synergism is seen at the concentration of 0,05 nM 1,25(OH)2D3 plus 100 nM 25OHD3, whereas at the "normal" physiological concentration of humans, 0,05 nM + 50 nM, respectively, there is a minimal induction. This result suggests that these cells begin to defend against too high dosage at a concentration of calcidiol within the range 50-100 nM. The results are in agreement with our earlier studies [7] that calcidiol has an inherent hormonal activity, but when it is acting alone, 250 nM concentration is needed. In vivo, the two hormones are acting in concert and they regulate negatively each other. Therefore, the serum concentration of 25OHD3 can be raised only moderately without decreasing intracellular concentration of 1,25(OH)2D3 and thereby the sum effect of the two calcipherol hormones. This suggests that there is an upper limit concentration for serum 25OHD3. In this respect, 25OHD3 does not differ from other hormones including retinoic acid. The upper limit concept is supported by some epidemiological data and aging studies summarized in a review [8]. The optimal 25OHD3 serum concentration based on the present knowledge seems to be 40-80 nmol/L, but the optimum might differ among different diseases and among different populations, therefore more studies are needed. An easy way to estimate maximal daily dose is to assaying serum 24OH metabolites. If 24OH metabolites increase, the dosage is too high.

The induction of 24-hydroxylation in vitamin D target cells suggests that the present way of oral administration of vitamin D3 may not be the most optimal. It is obvious that a single pill of vitamin D3 containing daily dose will cause a rapid increase of its serum concentration and consequently a peak concentration of 25OHD3. This activates, in turn, 24-hydroxylation reducing the efficiency of the treatment. Therefore, multiple small doses of vitamin D3 might be more optimal as used for many drugs. Alternatively, narrow band UV-B exposure should be considered. Sun exposure causes an even and moderate serum level of 25OHD3. The oral or topical treatment of psoriasis with highly active calcipotriol or â€“triene is the first phase cure for mild cases, but the more advanced diseases are treated with UV-B phototherapy. In these therapies vitamin D3 resistance should be taken into consideration..